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Editor-in-Chief | The drug resistance of malignant tumor cells is the fundamental reason why cancer cannot be completely cured.
A small part of residual tumor cells have become the root cause of cancer refractory/relapse due to their potential to escape the killing of drugs and immune systems.
The malignant tumor cells are called minimal residual disease (Minimal Residual Disease, MRD)
.
The study of MRD began with hematological malignancies, and it is an important indicator for treatment monitoring and prognostic evaluation of hematological malignancies
.
In recent years, with the development of next-generation sequencing technology, MRD detection methods including circulating tumor cells and circulating tumor DNA monitoring have also been widely used in MRD evaluation of solid tumors [1-5]
.
However, due to the lagging development of research techniques and other reasons, the mechanism of MRD is still unclear
.
On February 10, 2022, Zhu Xiaofan, Cheng Tao's team, and Tsinghua University Gujin's team jointly published the title Elucidating Minimal Residual Disease of Paediatric B in the journal Nature Cell Biology.
- Research paper on cell Acute Lymphoblastic Leukaemia by Single-cell Analysis
.
This study focused on childhood B-cell acute lymphoblastic leukemia (B-ALL), the most common hematological malignancy in children, and was the first in the world to use single-cell sequencing technology to map children's B-cell The single-cell atlas of ALL MRD found that abnormal activation of hypoxia signaling pathway is an important feature of B-ALL MRD cells in children, and hypoxia signaling pathway is a potential therapeutic target for children with relapsed and refractory B-ALL
.
By combining single-cell transcriptome sequencing and single-cell BCR sequencing technologies, the authors first mapped a reference single-cell map of childhood B-cell development using bone marrow mononuclear cells derived from healthy children's donors
.
By defining cells at different developmental stages from hematopoietic stem cells to mature B cells, identifying key genes in cells at different developmental stages, and establishing specific gene sets for cells at different developmental stages, it provides a reference for exploring the pathogenesis of leukemia cells
.
In the China Children's Cancer Research Collaborative Group's multi-center clinical study ALL-2015 program (CCCG-ALL-2015) enrolled by the Children's Hematology Center, the authors screened out the initial diagnosis - induction therapy (day 19, D19) - complete recurrence The remaining bone marrow samples of 4 children with B-ALL at consecutive time points were compared with the newly diagnosed bone marrow samples of 4 children without relapsed B-ALL as controls.
CD19+ cells were sorted for single-cell transcriptome and single-cell BCR sequencing
.
According to the BCR clonal diversity, the authors initially identified leukemia cells and normal B cells, and then used the characteristic tumor molecular markers of children for classification and verification, which confirmed the reliability of using BCR clonal diversity to identify leukemia cells
.
A machine learning model for the identification of leukemia cells was established using confirmed leukemia cells and normal cells
.
Using the characteristic gene set of B cell differentiation stage and leukemia cell machine learning model, the authors first compared the differences in differentiation stage, cell cycle, transcriptional regulation, key gene expression, etc.
between newly diagnosed and relapsed cells at the single-cell level.
Compared with the relapsed cells, the relapsed cells have the phenomenon of reverse differentiation, the MYC and other signaling pathways are activated, and the cell cycle regulatory protein P21 (CDKN1A) is significantly highly expressed in the relapsed cells.
The in vitro experiments show that knockdown of CDKN1A will increase B-ALL cell line chemotherapy drugs In addition, P21 small-molecule inhibitors can synergize with chemotherapeutic drugs to effectively kill B-ALL cells
.
By comparing the single-cell transcriptome data of leukemia cells in three stages of initial diagnosis, D19 and relapse, the authors found that the differentiation stage of residual leukemia cells has no significant characteristics, but the cell cycle is more in a quiescent state, and the hypoxia signaling pathway is significantly activated
.
D19 residual cells in three of the four patients showed activation of the hypoxic signaling pathway
.
Afterwards, the authors used in vitro and in vivo experimental models to confirm that the expression of HIF1α, a key regulatory protein of hypoxia signaling pathway, was increased after chemotherapeutic drug treatment, and the downstream signaling pathway was activated
.
The small molecule inhibitor PX478 against HIF1α can synergize chemotherapeutic drugs in vitro and in vivo to effectively kill B-ALL cell lines and primary B-ALL cells, thereby significantly prolonging the survival time of B-ALL PDX mice
.
This research uses single-cell sequencing technology to carry out in-depth research on MRD combined with unique clinical samples, which is the first time in the field of MRD research at home and abroad
.
The study found that the hypoxia signaling pathway was abnormally activated in the residual cell samples of B-ALL in children, which was verified in the experimental model in vitro and in vivo.
, provides a treatment plan with potential translational application value for children with B-ALL, and provides an important reference model for MRD research in other hematological malignancies and solid tumors
.
Professor Cheng Tao, Professor Zhu Xiaofan and Associate Professor Gu Jin of Tsinghua University are the corresponding authors of this paper
.
Zhang Yingchi, associate researcher at Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), Wang Shicheng (graduated), postgraduate student of Tsinghua University, Zhang Jing, attending physician of Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences) Yan, Ph.
D.
candidate Liu Chao (graduated) and Tsinghua University Ph.
D.
candidate Li Xinqi are the co-first authors of this article
.
Original link: https:// Publisher: Eleven References 1.
Hasserjian RP, Steensma DP, Graubert TA, Ebert BL.
Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia.
Blood.
2020 May 14;135(20):1729-1738.
.
2.
Della Starza, I.
, et al.
Minimal Residual Disease in Acute Lymphoblastic Leukemia: Technical and Clinical Advances.
Front Oncol 9, 726 (2019).
3.
Rambow, F.
, et al.
Toward Minimal Residual Disease-Directed Therapy in Melanoma.
Cell 174, 843-855 e819 (2018).
4.
Luskin, MR, Murakami, MA, Manalis, SR & Weinstock , DM Targeting minimal residual disease: a path to cure? Nat Rev Cancer 18, 255-263 (2018).
5.
Klaus Pantel , Catherine Alix-Panabières.
Liquid biopsy and minimal residual disease - latest advances and implications for cure.
Nat Rev Clin Oncol.
2019 Jul;16(7):409-424 Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be held accountable. .
A small part of residual tumor cells have become the root cause of cancer refractory/relapse due to their potential to escape the killing of drugs and immune systems.
The malignant tumor cells are called minimal residual disease (Minimal Residual Disease, MRD)
.
The study of MRD began with hematological malignancies, and it is an important indicator for treatment monitoring and prognostic evaluation of hematological malignancies
.
In recent years, with the development of next-generation sequencing technology, MRD detection methods including circulating tumor cells and circulating tumor DNA monitoring have also been widely used in MRD evaluation of solid tumors [1-5]
.
However, due to the lagging development of research techniques and other reasons, the mechanism of MRD is still unclear
.
On February 10, 2022, Zhu Xiaofan, Cheng Tao's team, and Tsinghua University Gujin's team jointly published the title Elucidating Minimal Residual Disease of Paediatric B in the journal Nature Cell Biology.
- Research paper on cell Acute Lymphoblastic Leukaemia by Single-cell Analysis
.
This study focused on childhood B-cell acute lymphoblastic leukemia (B-ALL), the most common hematological malignancy in children, and was the first in the world to use single-cell sequencing technology to map children's B-cell The single-cell atlas of ALL MRD found that abnormal activation of hypoxia signaling pathway is an important feature of B-ALL MRD cells in children, and hypoxia signaling pathway is a potential therapeutic target for children with relapsed and refractory B-ALL
.
By combining single-cell transcriptome sequencing and single-cell BCR sequencing technologies, the authors first mapped a reference single-cell map of childhood B-cell development using bone marrow mononuclear cells derived from healthy children's donors
.
By defining cells at different developmental stages from hematopoietic stem cells to mature B cells, identifying key genes in cells at different developmental stages, and establishing specific gene sets for cells at different developmental stages, it provides a reference for exploring the pathogenesis of leukemia cells
.
In the China Children's Cancer Research Collaborative Group's multi-center clinical study ALL-2015 program (CCCG-ALL-2015) enrolled by the Children's Hematology Center, the authors screened out the initial diagnosis - induction therapy (day 19, D19) - complete recurrence The remaining bone marrow samples of 4 children with B-ALL at consecutive time points were compared with the newly diagnosed bone marrow samples of 4 children without relapsed B-ALL as controls.
CD19+ cells were sorted for single-cell transcriptome and single-cell BCR sequencing
.
According to the BCR clonal diversity, the authors initially identified leukemia cells and normal B cells, and then used the characteristic tumor molecular markers of children for classification and verification, which confirmed the reliability of using BCR clonal diversity to identify leukemia cells
.
A machine learning model for the identification of leukemia cells was established using confirmed leukemia cells and normal cells
.
Using the characteristic gene set of B cell differentiation stage and leukemia cell machine learning model, the authors first compared the differences in differentiation stage, cell cycle, transcriptional regulation, key gene expression, etc.
between newly diagnosed and relapsed cells at the single-cell level.
Compared with the relapsed cells, the relapsed cells have the phenomenon of reverse differentiation, the MYC and other signaling pathways are activated, and the cell cycle regulatory protein P21 (CDKN1A) is significantly highly expressed in the relapsed cells.
The in vitro experiments show that knockdown of CDKN1A will increase B-ALL cell line chemotherapy drugs In addition, P21 small-molecule inhibitors can synergize with chemotherapeutic drugs to effectively kill B-ALL cells
.
By comparing the single-cell transcriptome data of leukemia cells in three stages of initial diagnosis, D19 and relapse, the authors found that the differentiation stage of residual leukemia cells has no significant characteristics, but the cell cycle is more in a quiescent state, and the hypoxia signaling pathway is significantly activated
.
D19 residual cells in three of the four patients showed activation of the hypoxic signaling pathway
.
Afterwards, the authors used in vitro and in vivo experimental models to confirm that the expression of HIF1α, a key regulatory protein of hypoxia signaling pathway, was increased after chemotherapeutic drug treatment, and the downstream signaling pathway was activated
.
The small molecule inhibitor PX478 against HIF1α can synergize chemotherapeutic drugs in vitro and in vivo to effectively kill B-ALL cell lines and primary B-ALL cells, thereby significantly prolonging the survival time of B-ALL PDX mice
.
This research uses single-cell sequencing technology to carry out in-depth research on MRD combined with unique clinical samples, which is the first time in the field of MRD research at home and abroad
.
The study found that the hypoxia signaling pathway was abnormally activated in the residual cell samples of B-ALL in children, which was verified in the experimental model in vitro and in vivo.
, provides a treatment plan with potential translational application value for children with B-ALL, and provides an important reference model for MRD research in other hematological malignancies and solid tumors
.
Professor Cheng Tao, Professor Zhu Xiaofan and Associate Professor Gu Jin of Tsinghua University are the corresponding authors of this paper
.
Zhang Yingchi, associate researcher at Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), Wang Shicheng (graduated), postgraduate student of Tsinghua University, Zhang Jing, attending physician of Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences) Yan, Ph.
D.
candidate Liu Chao (graduated) and Tsinghua University Ph.
D.
candidate Li Xinqi are the co-first authors of this article
.
Original link: https:// Publisher: Eleven References 1.
Hasserjian RP, Steensma DP, Graubert TA, Ebert BL.
Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia.
Blood.
2020 May 14;135(20):1729-1738.
.
2.
Della Starza, I.
, et al.
Minimal Residual Disease in Acute Lymphoblastic Leukemia: Technical and Clinical Advances.
Front Oncol 9, 726 (2019).
3.
Rambow, F.
, et al.
Toward Minimal Residual Disease-Directed Therapy in Melanoma.
Cell 174, 843-855 e819 (2018).
4.
Luskin, MR, Murakami, MA, Manalis, SR & Weinstock , DM Targeting minimal residual disease: a path to cure? Nat Rev Cancer 18, 255-263 (2018).
5.
Klaus Pantel , Catherine Alix-Panabières.
Liquid biopsy and minimal residual disease - latest advances and implications for cure.
Nat Rev Clin Oncol.
2019 Jul;16(7):409-424 Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be held accountable. .
